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Published March 13, 2001 | Published
Journal Article Open

RPN4 is a ligand, substrate, and transcriptional regulator of the 26S proteasome: A negative feedback circuit


The RPN4 (SON1, UFD5) protein of the yeast Saccharomyces cerevisiae is required for normal levels of intracellular proteolysis. RPN4 is a transcriptional activator of genes encoding proteasomal subunits. Here we show that RPN4 is required for normal levels of these subunits. Further, we demonstrate that RPN4 is extremely short-lived (t(1/2) approximate to 2 min), that it directly interacts with RPN2, a subunit of the 26S proteasome, and that rpn4 Delta cells are perturbed in their cell cycle. The degradation signal of RPN4 was mapped to its N-terminal region, outside the transcription-activation domains of RPN4. The ability of RPN4 to augment the synthesis of proteasomal subunits while being metabolically unstable yields a negative feedback circuit in which the same protein up-regulates the proteasome production and is destroyed by the assembled active proteasome.

Additional Information

© 2001 by the National Academy of Sciences. Contributed by Alexander Varshavsky, January 16, 2001. We are grateful to Xiaofeng Qin and Wenge Lu for advice and assistance with flow cytometric analysis, to Christopher Byrd (California Institute of Technology), Jurgen Dohmen (University of Cologne, Cologne, Germany), Mark Hochstrasser (Yale University, New Haven, CT), Jon Huibregtse (Rutgers University, Piscataway, NJ), Erica Johnson (Thomas Jefferson University, Philadelphia, PA), Yoshiko Kikuchi (University of Tokyo, Tokyo, Japan), Robert Swanson (University of Chicago, Chicago, IL), Glenn Turner (California Institute of Technology), and Fred Winston (Harvard Medical School, Boston, MA) for strains and constructs, and to Keiji Tanaka (Institute of Medical Science, Tokyo) for anti-RPN4 antibody. This work was supported by grants to A.V. from the National Institutes of Health (NIH) (DK39520 and GM31530). Y.X. was supported in part by a postdoctoral fellowship from the NIH. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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August 21, 2023
October 13, 2023